Traditional approaches to reaction discovery typically focus on one particular chemical transformation. Predicted precursors for a target structure are chosen as substrates, and then particular reaction conditions are evaluated either manually or in a high-throughput format (Stambuli et al. Recent advances in the discovery of organometallic catalysts using high-throughput screening assays. Curr. Opin. Chem. Biol. 7, 420-426 (2003); Reetz, Combinatorial and evolution-based methods in the creation of enantioselective catalysts. Angew. Chem. Int. Ed. 40, 284-310 (2001); Stambuli et al. Screening of homogeneous catalysts by fluorescence resonance energy transfer. Identification of catalysts for room-temperature Heck reactions. J. Am. Chem. Soc. 123, 2677-8 (2001); Taylor et al. Thermographic selection of effective catalysts from an encoded polymer-bound library. Science 280, 267-70 (1998); Lober et al. Palladium-catalyzed hydroamination of 1,3-dienes: a colorimetric assay and enantioselective additions. J. Am. Chem. Soc. 123, 4366-7 (2001); Evans et al. Proton-activated fluorescence as a tool for simultaneous screening of combinatorial chemical reactions. Curr. Opin. Chem. Biol. 6, 333-338 (2002); each of which is incorporated herein by reference) for their ability to produce the desired target product. Although this approach is very useful in addressing specific chemical problems, it does not lend itself to the discovery of entirely new chemical reactions. In fact, its focused nature may leave many areas of chemical reactivity unexplored.
Recent developments in DNA-templated synthesis suggest that DNA annealing can organize many substrates in a single solution into DNA sequence-programmed pairs. DNA-templated synthesis and in vitro selection may, therefore, be used to evaluate many combinations of substrates and conditions for bond-forming reactions (Calderone et al. Directing otherwise incompatible reactions in a single solution by using DNA-templated organic synthesis. Angew. Chem. Int. Ed. 41, 4104-8 (2002); Gartner et al. The generality of DNA-templated synthesis as a basis for evolving non-natural small molecules. J. Am. Chem. Soc. 123, 6961-3 (2001); Gartner et al. Expanding the reaction scope of DNA-templated synthesis. Angew. Chem. Int. Ed. 41, 1796-1800 (2002); Rosenbaum et al. Efficient and Sequence-Specific DNA-Templated Polymerization of Peptide Nucleic Acid Aldehydes. J. Am. Chem. Soc. 125, 13924-5 (2003); each of which is incorporated herein by reference). See also published U.S. patent application 2004/018042, published Sep. 16, 2004, which is incorporated herein by reference. Watson-Crick base pairing controls the effective molarities of substrates tethered to DNA strands. Selection for bond formation, amplification by PCR, and DNA array analysis then reveals bond-forming substrate combinations and conditions. The versatility and efficiency of DNA-templated synthesis enables the discovery of reactions between substrates typically thought to be unreactive.
DNA-templated synthesis has now been used to discover new chemical reactions that are potentially broadly useful in the synthesis of chemical compounds such as pharmaceutical agents, new materials, polymers, catalysts, etc. In particular, a DNA-templated reaction discovery system has been used to discover a novel palladium-catalyzed carbon-carbon bond forming reaction. See U.S. patent application Ser. No. 11/205,493, filed Aug. 17, 2005; Kanan et al. “Reaction Discovery Enabled by DNA-Templated Synthesis and In Vitro Selection” Nature 431, 545-549 (2004); each of which is incorporated herein by reference. However, the need for DNA hybridization in the reaction discovery system limits the reaction conditions that can be explored. Duplex formation typically requires an aqueous solution with a relatively high salt concentration. Although water has been used extensively as a solvent for organic reactions (Li & Chan, Organic Reactions in Aqueous Media John Wiley & Sons, Inc., 1997; incorporated herein by reference), many ligands, catalysts, and reagents are insoluble in water. To access more traditional organic and organometallic chemistry reaction conditions in a selection-based approach to reaction discovery, alternative systems for organizing pairs of substrates in a single solution need to be explored.